Ranger™ Paclitaxel-Coated PTA Balloon Catheter

P190019 · Boston Scientific Corporation · ONU · Oct 30, 2020 · Cardiovascular

Device Facts

Record IDP190019
Device NameRanger™ Paclitaxel-Coated PTA Balloon Catheter
ApplicantBoston Scientific Corporation
Product CodeONU · Cardiovascular
Decision DateOct 30, 2020
DecisionAPPR
Device ClassClass 3
AttributesTherapeutic

Indications for Use

The Ranger Paclitaxel-Coated PTA Balloon Catheter is indicated for percutaneous transluminal angioplasty (PTA) of de novo or restenotic lesions up to 180 mm in length located in native superficial femoral and proximal popliteal arteries (SFA/PPA) with reference vessel diameters of 4 - 7 mm.

Device Story

Ranger DCB is a sterile, single-use, over-the-wire drug-coated balloon catheter used in peripheral vascular interventions. It combines mechanical dilatation of stenotic lesions in the SFA/PPA with local delivery of paclitaxel to inhibit neointimal proliferation and reduce restenosis. The device is operated by physicians in a clinical setting. The balloon is coated with paclitaxel (2 µg/mm²) and an acetyl tributyl citrate (ATBC) excipient. Upon inflation, the balloon expands to establish vessel patency while transferring the drug to the arterial wall. The physician monitors the procedure via fluoroscopy using radiopaque marker bands. The device benefits patients by reducing the need for repeat revascularization compared to standard PTA. It is compatible with 0.014"/0.018" guidewires.

Clinical Evidence

Pivotal RANGER II SFA trial (N=376, 3:1 randomization) compared Ranger DCB to standard PTA. Primary safety endpoint (12-month MAE-free rate) was 94.1% (Ranger) vs 83.5% (PTA), meeting non-inferiority (p<0.0001). Primary effectiveness endpoint (12-month primary patency) was 82.9% (Ranger) vs 66.3% (PTA), demonstrating superiority (p=0.0017). Long-term mortality data (up to 3 years) evaluated via Kaplan-Meier and Bayesian predictive modeling showed no unacceptable mortality risk compared to marketed paclitaxel-coated devices.

Technological Characteristics

Drug-coated PTA balloon catheter; paclitaxel API (2 µg/mm²) with ATBC excipient. Materials: Uncoated PTA balloon catheter (externally communicating, limited contact) and drug-coated balloon (implant, permanent contact). Sterilization: Ethylene oxide (EO) per ISO 11135. Compatible with 0.014"/0.018" guidewires. Radiopaque marker bands for fluoroscopic visualization. Rated burst pressure: 14 atm.

Indications for Use

Indicated for patients ≥ 20 years old with chronic symptomatic lower limb ischemia (Rutherford 2-4) requiring PTA of de novo or restenotic lesions (≤ 180 mm length) in native SFA/PPA (4-7 mm diameter). Contraindicated in patients with known hypersensitivity to paclitaxel, those unable to receive antiplatelet/anticoagulation therapy, pregnant/breastfeeding women, men intending to father children, or patients with lesions preventing complete balloon inflation.

Regulatory Classification

Identification

A drug-eluting peripheral transluminal angioplasty catheter is a combination product intended for balloon dilatation of peripheral vasculature to establish or maintain patency. A drug-eluting PTA catheter delivers a drug to the vessel as part of the angioplasty procedure and is intended to inhibit restenosis. Intended to provide percutaneous transluminal angioplasty of lesions in peripheral arteries including iliac, popliteal, femoral, and iliofemoral.

Reference Devices

Related Devices

Submission Summary (Full Text)

{0} SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED) I. GENERAL INFORMATION Device Generic Name: Drug-Eluting Peripheral Transluminal Angioplasty Catheter Device Trade Name: Ranger™ Paclitaxel-Coated PTA Balloon Catheter Device Procode: ONU Applicant’s Name and Address: Boston Scientific Corporation Three Scimed Place Maple Grove, MN 55311 Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P190019 Date of FDA Notice of Approval: October 30, 2020 II. INDICATIONS FOR USE The Ranger Paclitaxel-Coated PTA Balloon Catheter is indicated for percutaneous transluminal angioplasty (PTA) of de novo or restenotic lesions up to 180 mm in length located in native superficial femoral and proximal popliteal arteries (SFA/PPA) with reference vessel diameters of 4 - 7 mm. III. CONTRAINDICATIONS The Ranger Paclitaxel-Coated PTA Balloon Catheter is contraindicated for use in patients - With known hypersensitivity to paclitaxel (or structurally-related compounds). - Patients who cannot receive recommended antiplatelet and/or anticoagulation therapy - Women who are breastfeeding, pregnant or are intending to become pregnant or men intending to father children - Coronary arteries, renal arteries, and supra-aortic/cerebrovascular arteries - Patients judged to have a lesion that prevents complete inflation of an angioplasty balloon or proper placement of the delivery system PMA P190019: FDA Summary of Safety and Effectiveness Data Page 1 of 51 {1} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 2 of 51 # IV. WARNINGS AND PRECAUTIONS A signal for increased risk of late mortality has been identified following the use of paclitaxel-coated balloons and paclitaxel-eluting stents for femoropopliteal arterial disease beginning approximately 2-3 years post-treatment compared with the use of non-drug coated devices. There is uncertainty regarding the magnitude and mechanism for the increased late mortality risk, including the impact of future device exposure. Physicians should discuss this late mortality signal and the benefits and risks of available treatment options with their patients. Additional warnings and precautions can be found in the Ranger™ Paclitaxel-Coated PTA Balloon Catheter labeling. # V. DEVICE DESCRIPTION The Ranger Paclitaxel-Coated PTA Balloon Catheter (Ranger DCB) (Figure 1) is a sterile, single-use, over-the-wire (OTW) device/drug combination product comprised of two regulated components: - Uncoated PTA Balloon Catheter: Percutaneous transluminal angioplasty balloon catheter uses mechanical force of balloon expansion across a lesion to establish patency - Balloon Drug Coating: A formulation of the active pharmaceutical ingredient paclitaxel with an excipient, to serve as an adjunct to the mechanical action of balloon angioplasty by reducing restenosis and repeat revascularization rates at the treatment site ![img-0.jpeg](img-0.jpeg) Figure 1: Schematic of the Ranger DCB PTA Catheter Component The Ranger DCB is available in multiple balloon sizes and catheter working lengths, as listed in Table 1, and is compatible with 0.014" / 0.018" guidewires. {2} Table 1: Ranger DCB Product Matrix | Balloon Diameter (mm) | Balloon Length (mm) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | 30 | 40 | 60 | 80 | 100 | 120 | 150 | 200 | | 4.0 | X | X | X | X | X | X | X | X | | 5.0 | X | X | X | X | X | X | X | X | | 6.0 | X | X | X | X | X | X | X | X | | 7.0 | X | X | X | X | X | X | X | X | Note: Catheters are available in working lengths of 80 and 135 cm (balloon lengths 30 – 100 mm) and 90 and 150 cm (balloon lengths 120 – 200 mm) ## Drug Component The proprietary Ranger DCB TransPax™ coating consists of active pharmaceutical paclitaxel at a nominal drug dose density of 2 µg/mm² of balloon surface, and acetyl tributyl citrate (ATBC) excipient which provides drug coating durability and drug transfer to the vessel wall upon balloon expansion. Based on the nominal drug dose density of 2 µg/mm², the total amount of paclitaxel for each balloon size is provided in Table 2. Table 2: Nominal Paclitaxel Content by Balloon Size | Balloon Diameter (mm) | Balloon Length (mm) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | 30 | 40 | 60 | 80 | 100 | 120 | 150 | 200 | | 4.0 | 782 µg | 1043 µg | 1564 µg | 2086 µg | 2607 µg | 3100 µg | 3878 µg | 5165 µg | | 5.0 | 975 µg | 1301 µg | 1951 µg | 2601 µg | 3251 µg | 3978 µg | 4942 µg | 6592 µg | | 6.0 | 1100 µg | 1467 µg | 2200 µg | 3108 µg | 3889 µg | 4809 µg | 5975 µg | 7966 µg | | 7.0 | 1283 µg | 1711 µg | 2714 µg | 3626 µg | 4538 µg | 5564 µg | 6958 µg | 9266 µg | ## Active Pharmaceutical Ingredient (API) – Paclitaxel The API of the Ranger DCB is paclitaxel. The principal mechanism by which paclitaxel inhibits neointimal growth is through the stabilization of microtubules by preventing their depolymerization during the final G2/M phase of cell division. The CAS Registry number of paclitaxel is 33069-62-4. The systematic IUPAC chemical name is (2aR-(2aα,4β,4aβ,6β,9α(α R*,βS*),11α,12α,12bα))-β-(Benzoylamino)- α-hydroxybenzenepropanoic acid 6,12b-bis(acetyloxy)-12-(benzoyloxy)-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,11-methano-1H-cyclodeca(3,4)benz(1,2-b)oxet-9-yl ester, and the chemical formula is C₄₇H₅₁NO₁₄. The chemical structure of paclitaxel is illustrated in Figure 2. PMA P190019: FDA Summary of Safety and Effectiveness Data {3} ![img-1.jpeg](img-1.jpeg) Figure 2: Paclitaxel Chemical Structure # Excipient - Acetyl Tributyl Citrate (ATBC) The plasticizer ATBC is used as an excipient to facilitate delivery and transfer of the active pharmaceutical ingredient (paclitaxel) from the balloon to the arterial vessel wall upon balloon expansion. The chemical structure of ATBC is shown in Figure 3 below. ![img-2.jpeg](img-2.jpeg) Figure 3: ATBC Chemical Structure # Mechanism of Action The primary mode of action for the Ranger DCB is mechanical dilatation of de novo lesions by means of percutaneous transluminal angioplasty, with a secondary action of reducing neointimal proliferation from vessel injury due to PTA, and thereby reducing the rate of restenosis, through the application of paclitaxel to the arterial vessel wall. PMA P190019: FDA Summary of Safety and Effectiveness Data {4} # VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of superficial femoral (SFA) and popliteal artery atherosclerotic disease, including: Non-invasive treatment (risk factor modification, exercise, and/or drug therapy) - Minimally invasive treatment (balloon angioplasty, bare metal or drug-eluting stent, or plaque debulking by atherectomy) - Surgical treatment (surgical bypass) Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. # VII. MARKETING HISTORY The Ranger Paclitaxel-Coated PTA Balloon Catheter (Ranger DCB) has been available for distribution in the European Union (EU) since receiving CE Mark in July 2014 for balloon lengths 30 to $100\mathrm{mm}$ , with balloon lengths 120 to $200\mathrm{mm}$ receiving CE Mark in July 2017. The Ranger DCB has not been withdrawn from marketing from any region. The Ranger DCB is available for commercial distribution in the 69 countries listed in Table 3 with a general peripheral indication. Table 3: Commercial Availability of the Ranger DCB | Argentina | Armenia | Australia | Austria | Bahrain | Bangladesh | | --- | --- | --- | --- | --- | --- | | Belgium | Brunei | Bulgaria | Canada | Chile | Colombia | | Costa Rica | Croatia | Czech Republic | Denmark | Dominican Republic | Egypt | | El Salvador | Finland | France | Germany | Great Britain | Greece | | Hong Kong | Hungary | India | Indonesia | Ireland | Israel | | Italy | Jordan | Kuwait | Latvia | Lebanon | Lithuania | | Macedonia | Malaysia | Malta | Mexico | Morocco | Netherlands | | New Zealand | Norway | Oman | Pakistan | Palestinian territories | Panama | | Paraguay | Peru | Philippines | Poland | Portugal | Romania | | Saudi Arabia | Singapore | Slovakia | Slovenia | South Africa | South Korea | | Spain | Sweden | Switzerland | Taiwan | Thailand | Turkey | | United Arab Emirates | Uruguay | Vietnam | | | | PMA P190019: FDA Summary of Safety and Effectiveness Data {5} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 6 of 51 # VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Potential adverse effects (e.g., complications) which may be associated with the use of Ranger Paclitaxel-Coated PTA Balloon Catheter (Ranger DCB) include, but are not limited to: - Allergic reaction (device, contrast medium, medications) - Arteriovenous fistula - Death - Hemorrhage / Bleeding - Hypotension / Hypertension - Infection / Sepsis - Pseudoaneurysm - Thromboembolic episodes - Vascular thrombosis - Vessel injury (e.g., dissection, perforation, rupture) - Vessel occlusion - Vessel spasm Potential adverse effects, not captured above, that may be due to systemic administration of paclitaxel, include, but are not limited to, the following: - Allergic / immunologic reaction to drug (paclitaxel or structurally-related compounds) or coating or its individual components - Alopecia - Anemia - Blood product transfusion - Gastrointestinal symptoms - Hematologic dyscrasia (including leukopenia, neutropenia, thrombocytopenia) - Hepatic enzyme changes - Histologic changes in vessel wall, including inflammation, cellular damage or necrosis - Myalgia/Arthralgia - Peripheral neuropathy Apart from hypersensitivity reactions (allergic / immunologic reactions), the likelihood of paclitaxel related adverse events is low, due to the low exposure. {6} For the specific adverse events that occurred in the clinical study, please see Section X.D below. # IX. SUMMARY OF NON-CLINICAL STUDIES A series of non-clinical laboratory studies related to the product were performed to evaluate the device, including: biocompatibility studies, in vitro engineering testing, coating characterization testing, analytical pharmaceutical testing, packaging testing, stability and shelf life testing, sterilization, and Good Laboratory Practice (GLP) animal studies. A summary for each of the evaluations is provided below. # A. Biocompatibility Studies Biocompatibility testing of the Ranger Paclitaxel-Coated PTA Balloon Catheter (Ranger DCB) was conducted separately on uncoated Ranger PTA balloon catheters and on isolated balloon components containing drug coating. For the purposes of this testing, the uncoated Ranger PTA balloon catheter was categorized as an externally communicating device with limited contact duration (&lt;24 hours) with circulating blood, and the balloon component with drug coating was categorized as an implant device with permanent blood contact (&gt;30 days). In addition, chemical characterization was conducted in vitro on both uncoated and drug-coated balloon components. The endpoints of sub-acute (sub-chronic) toxicity, chronic toxicity, and implantation were evaluated using coated Ranger PTA balloon catheters as part of in vivo studies conducted to evaluate the safety and effectiveness of the device in porcine iliofemoral artery model, as described in Section IX.H, Animal Studies, below. These additional animal studies demonstrated a lack of inflammation and toxicity when the product was used in a clinically-relevant vascular location. Chemical characterization and toxicological risk assessments were also conducted to support sub-acute (sub-chronic) toxicity, chronic toxicity, genotoxicity, and carcinogenicity endpoints. The information provided demonstrates that the Ranger DCB is biocompatible for its intended use. A summary of the biocompatibility testing and results can be found in Table 4. Table 4: Summary of Biocompatibility Testing | Test / ISO Reference | Test Name | Uncoated Catheter | Coated Balloon | Results | | --- | --- | --- | --- | --- | | Cytotoxicity ISO 10993-5 | MEM Endpoint Dilution Assay | X | X | Non-cytotoxic for uncoated catheter; acceptable response for coated balloon* | | | Direct Cytotoxicity | -- | X | Non-cytotoxic | | Sensitization ISO 10993-10 | Guinea Pig Maximization | X | X | Non-sensitizing | | Irritation | Intracutaneous | X | X | Non-irritant | PMA P190019: FDA Summary of Safety and Effectiveness Data {7} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 8 of 51 | ISO 10993-10 | Reactivity | | | | | --- | --- | --- | --- | --- | | Systemic Toxicity ISO 10993-11 | Acute Systemic Toxicity | X | X | Non-toxic | | | Sub-acute (Sub-chronic) Systemic Toxicity | Catheter + drug-coated balloon | | Non-toxic# | | | Chronic Systemic Toxicity | Catheter + drug-coated balloon | | Non-toxic# | | Pyrogenicity ISO 10993-11 | Material-Mediated Rabbit Pyrogenicity | X | X | Non-pyrogenic | | Implantation ISO 10993-6 | Implantation | Catheter + drug-coated balloon | | Acceptable local tissue response# | | Hemocompatibility ISO 10993-4 | Hemolysis Direct Contact | X | X | Non-hemolytic | | | Hemolysis Extract Method | X | X | Non-hemolytic | | | Complement Activation C3a and SC5b-9 | X | X | Not a complement activator | | | In vivo thrombogenicity | Catheter + drug-coated balloon | | Non-thrombogenic# | | Chemical Characterization ISO 10993-18 | Exhaustive Extraction and Analysis by GC/MS, LC/MS, ICP/MS | X (balloon only) | X | Extractables do not pose toxicity concerns for the endpoints of carcinogenicity, genotoxicity, and subchronic/chronic systemic toxicity. | * Cytotoxic response from the neat extract of the balloon, but considered acceptable after extract dilution and based on acceptable implantation response from the GLP safety study, noted in Section H below. # Endpoint was assessed in the GLP safety study, as noted in Section H below. # B. In Vitro Bench Testing An overview of the functional engineering testing performed on the Ranger DCB is provided in Table 5. The table includes the test performed, the objective of the tests, the acceptance criteria (as applicable), and the result of the test. Table 5: Summary of Functional Testing Performed | Test | Testing Objective | Acceptance Criteria (Specification) | | | | Pass / Fail | | --- | --- | --- | --- | --- | --- | --- | | Catheter Profiles | Demonstrate the catheter inner diameter (ID) and outer diameter (OD) meets the | OD: The catheter profiles (mm) must be: | | | | Pass | | | | Balloon Diameter | Max Crossing Profile | Shaft Profile | | | | | | 4 | ≤1.78 | Characterization only | | | {8} | Test | Testing Objective | Acceptance Criteria (Specification) | | | | | Pass / Fail | | --- | --- | --- | --- | --- | --- | --- | --- | | | labeled values | 5 | ≤1.78 | Characterization only | | | | | | | 6 | ≤1.88 | Characterization only | | | | | | | 7 | ≤2.20 | Characterization only | | | | | | | ID: The device accommodates 0.018” guidewires | | | | | | | Catheter Working Length | Demonstrate the catheter working length (manifold strain relief to distal end) meets the labeled value | 80, 90, 135, 150 ± 2.5 cm | | | | | Pass | | Balloon Body Length | Demonstrate the balloon working body length meets the labeled value when inflated to nominal pressure | The balloon working length (mm) must be: | | | | | Pass | | | | Nominal Balloon Length | Min | Max | | | | | | | 30 | 28 | 32 | | | | | | | 40 | 38 | 42 | | | | | | | 60 | 57 | 63 | | | | | | | 80 | 76 | 84 | | | | | | | 100 | 95 | 105 | | | | | | | 120 (4mm diameter) | 114 | 126 | | | | | | | 120 (all others) | 116 | 124 | | | | | | | 150 (4mm diameter) | 142.5 | 157.5 | | | | | | | 150 (all others) | 145 | 155 | | | | | | | 200 | 195 | 205 | | | | | Balloon Preparation, Deployment and Retraction | Demonstrate the catheter can be safely and reliably prepared, inflated/deflated, and retracted using the recommended techniques in the Instructions for Use without damage to the product | Devices must be prepared, tracked through an anatomically relevant model, inflated/deflated, and withdrawn without damage to the catheter | | | | | Pass | | Balloon Rated Burst Pressure | Demonstrate the catheter can withstand inflation pressures that exceed the labeled balloon burst pressures | No part of the device shall fail at or below the rated burst pressure (atm): | | | | | Pass | | | | Balloon Diameter | Rated Burst Pressure | | | | | | | | 4 – 7 mm | 14 | | | | | | Repeat Inflation | Demonstrate the catheter can withstand | The catheter must withstand 10 repeat inflations to rated burst pressure without failure | | | | | Pass | PMA P190019: FDA Summary of Safety and Effectiveness Data {9} | Test | Testing Objective | Acceptance Criteria (Specification) | Pass / Fail | | --- | --- | --- | --- | | | multiple inflations to RBP | | | | Balloon Compliance | Demonstrate the balloon diameter meets the labeled compliance values with increasing pressure | The balloon diameters must be: | Pass | | Balloon Diameter | Difference from Labelled | | 4 - 5 mm | ≤ 18% | | 6 - 7 mm | ≤ 15% | | Balloon Inflation / Deflation Time | Demonstrate the balloon inflates and deflates within clinically acceptable time limits | Inflation: This test is for characterization onlyDeflation: The deflation time from rated burst pressure must be ≤ 60 seconds | Pass | | Bond Tensile Strength: a) Manifold b) Proximal Balloon c) Outer Shaft at Tack Weld d) Tip | Demonstrate the catheter can withstand tensile strength requirements of the catheter bonds after pre-conditioning | The catheter must withstand the tensile forces (lbf): | Pass | | Balloon Diameter / Length | Shaft Type | Manifold | Proximal Balloon & Tack Weld | Tip | | 4 x all | 4F | ≥ 2.95 | ≥ 3.14 | 0.5 | | 5 x ≤100 | | 6 x ≤60 | | 7 x ≤40 | | 5 x ≥120 | 4/5F Hybrid | ≥ 3.18 | ≥ 3.38 | 0.5 | | 6 x ≥80 | | 7 x ≥60 | | Kink Resistance | Demonstrate the catheter can withstand flexural forces without kinking after pre-conditioning | The shaft must not kink at the specified diameter (mm): | Pass | | Balloon Diameter / Length | Shaft Type | Kink Diameter | | 4 x all | 4F | ≥ 18.0 | | 5 x ≤100 | | 6 x ≤60 | | 7 x ≤40 | | 5 x ≥120 | 4/5F Hybrid | ≥30.0 | | 6 x ≥80 | | 7 x ≥60 | | Kink to Failure | Demonstrate the minimum diameter at which the catheter will kink | This test is for characterization only | N/A | | Torque Strength | Demonstrate the catheter maintains | This test is for characterization only | N/A | PMA P190019: FDA Summary of Safety and Effectiveness Data {10} | Test | Testing Objective | Acceptance Criteria (Specification) | Pass / Fail | | --- | --- | --- | --- | | | integrity when subjected to torsional forces | | | | Torque to Failure | Demonstrate the failure point of the catheter while applying torque | This test is for characterization only | N/A | | Radiopacity | Demonstrate the marker bands are fluoroscopically visible | The marker bands must be visible under fluoroscopy imaging | Pass | # C. Coating Characterization Testing Analytical testing was performed to evaluate characteristics of the Ranger DCB drug coating as summarized in Table 6 below. Table 6: Summary of Ranger DCB Coating Characterization | Test | Description | | --- | --- | | Particulates (Simulated Use) | Characterize the total counts and sizes of particulates generated from the drug coated balloon in simulated use conditions | | Particulate Identity and Crystallinity Characterization | Characterize chemical composition and crystallinity of particulates | | Drug Coating Thickness | Characterize coating thickness of the balloon at multiple locations along the length and circumference of the balloon | | Drug Coating Circumferential Uniformity | Measure the uniformity of drug content of multiple circumferential segments of finished Ranger DCB | | Drug Coating Longitudinal Uniformity | Measure the uniformity of drug content of multiple longitudinal segments, depending on balloon length, of finished Ranger DCB | | Drug Coating Durability | Durability and any performance impact to durability, is manifested in an assessment of drug content. Cohesion and adhesion of the coating is assessed in the measurement of drug content after the following steps: 1. Insertion through a guide sheath 2.Track through simulated anatomy | | Crystallinity Characterization | Characterize degree of crystallinity of the coating | | Drug Coating Integrity | Characterize drug coating Integrity including quantification of coated area | # D. Chemistry, Manufacturing and Controls (CMC) Testing The established requirements for ongoing Ranger DCB release batch and stability testing are summarized in Table 7. PMA P190019: FDA Summary of Safety and Effectiveness Data {11} Table 7: Ranger DCB CMC Testing Requirements | Test | Description | Acceptance Criteria | | --- | --- | --- | | Appearance | Packaging securement and appearance of the balloon coating appearance is evaluated by visual inspection | Must meet visual standard | | Drug Identity | The identity of the drug substance, paclitaxel, is confirmed by HPLC analysis and its UV spectrum | Identity must be confirmed via two different tests | | Drug Content Assay | Paclitaxel content is quantified by high performance liquid chromatography (HPLC) to ensure product contains the labeled dose | 90 – 110% of label claim | | Drug Content Uniformity | Paclitaxel content is quantified by HPLC to ensure individual devices contain the labeled dose | USP <905> | | Drug Degradants and Impurities | The levels of drug degradants and impurities are quantified by HPLC to ensure they remain within acceptable levels | ICH Q3B(R2) | | Residual Acetone Content | The residual acetone from the manufacturing process is quantified gas chromatography – flame ionization detector (GC-FID) to ensure it remains within acceptable levels | Residual acetone levels must be within limits | | Drug Release | The release paclitaxel quantified by HPLC to ensure it is within limits | USP <711> | | Device Sterility | The sterility of the single-use device is evaluated per USP <71> | USP <71> | | Endotoxins | Endotoxin levels are evaluated per AAMI ST72 to ensure they are within established safety guidelines | AAMI ST72 | | Particulates | The release particulate matter is evaluated by USP <788> to ensure it is within limits | Particulate sizes and counts must be within limits | E. Packaging Testing Packaging verification testing was performed to demonstrate that the Ranger DCB packaging can withstand the hazards of the distribution environment, and that the sterility of the device is maintained throughout the labeled shelf life. Package integrity testing included a visual assessment, bubble leak testing, and seal strength testing. Testing was conducted on both packaging at the baseline condition and packaging aged to the product shelf life. F. Stability/Shelf Life Testing A stability study was conducted according to International Conference on Harmonization (ICH) guidelines on Ranger DCB finished product to establish shelf life. The testing included drug coating appearance, drug assay, drug impurities and degradants, drug release, particulates, sterility, and endotoxin. PMA P190019: FDA Summary of Safety and Effectiveness Data {12} Shelf life engineering and packaging testing was also performed on aged product to demonstrate the device and packaging performs within specifications throughout the product shelf life. The data generated from the stability and shelf life studies currently supports the 18-month labeled shelf life. ## G. Sterilization The Ranger DCB is sterilized using ethylene oxide (EO) gas and has been validated per AAMI / ANSI / ISO 11135:2007, Sterilization of health care products - Ethylene oxide - Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices. Results from the sterilization studies demonstrate the product satisfies a minimum Sterility Assurance Level (SAL) of $10^{-6}$ and residual EO levels were within acceptable ranges in accordance with EN ISO 10993-7:2008, Biological Evaluation of Medical Devices - Part 7: Ethylene Oxide Sterilization Residuals. ## H. Animal Studies The following in vivo animal testing was conducted in a porcine iliofemoral artery model to evaluate the safety of the Ranger DCB: - One pharmacokinetic (PK) study was completed evaluating drug content in blood (time points from 0.5 hours to 60 days), treated iliofemoral arterial tissue, and downstream muscle/organ specimens (time points from 4 hours to 60 days) in swine. - One safety study was completed (time points from 7 to 180 days) providing evidence of drug delivery, tissue response, and safety in swine iliofemoral arteries. - One acute performance study was completed evaluating device performance and the potential for thrombus formation in swine iliofemoral arteries. All animal studies were conducted in accordance with 21 CFR 58 (Good Laboratory Practices). In addition to the principal endpoints noted for each study, all animals were carefully evaluated for general health (i.e. vital signs, behavior, nutritional condition, gait, etc.) and clinical responses to treatment. A list and description of the animal studies conducted is presented in Table 8. PMA P190019: FDA Summary of Safety and Effectiveness Data Page 13 of 51 {13} Table 8: Summary of In Vivo Ranger DCB Animal Studies | Study ID | Number & Animal Type | Local Drug Dose | Balloon Size | Time Points | Major Endpoints | Endpoints Met | | --- | --- | --- | --- | --- | --- | --- | | 15-018G Pharmacokinetic | n=36 Domestic Swine | 1x | 5-7 x 80 mm | Tissue 4 hours, 1/3/5/7/14/21/42/60 days | • Quantitative Angiography • Clinical Health • Arterial, Non-Target Tissue, and Blood levels | Yes | | | | | | Blood Baseline, 30 minutes, 1/4/8/hours, 1/2/3/5/7/14/21/42/60 days | | | | 15-017G Vascular Response | n=54 Domestic Swine | 1x, 3x | 5-8 x 80 mm | 7/30/90/180 days | • Quantitative Angiography • Clinical Safety • Histological Morphometric and Morphologic analysis • SEM Analysis | Yes | | 16-041G Acute Performance | n=2 Domestic Swine | 1x | 6-7 x 80 mm | Acute | • Clinical Safety and Device Performance | Yes | The preclinical studies conducted demonstrate and confirm the safety of treatment with the Ranger DCB. The GLP safety evaluation study of the Ranger DCB demonstrated favorable safety parameters as defined by the following: - Successful delivery of the device to the target treatment location without major procedural or device related complications, such as acute thrombosis, major bleeding, or flow-limiting dissection. - No morbidity or mortality device-related complications during the treatment procedures and in-life phases of the experiments. - No major angiographic differences observed between test and control treatment groups. No major vessel abnormalities were reported. Angiographic flow and stenosis were similar across treatment arms (1X, 3X, and Uncoated Balloon). - The histological morphometric assessments of the treated iliofemoral arteries were generally comparable across treatment arms (1X, 3X, and Uncoated Balloon) including EEL, IEL, lumen, medial, and neointimal areas, neointimal thickness and percent stenosis. There were no incidences of thrombotic occlusion or aneurysmal formation out to 180 days. - Comparable histological indicators of vessel wall healing such as: injury, inflammation, and fibrosis with the test articles (1X, 3X) when compared to PMA P190019: FDA Summary of Safety and Effectiveness Data {14} control tissue sections. The extent of endothelial coverage as determined by light microscopy and/or scanning electron microscopy (SEM) in tissue sections were comparable between arms with endothelization nearly complete by 30 days and no abnormal findings on any endothelial surface. - Downstream non-target tissues including skeletal muscle and organs showed no clinically relevant device related events. The preclinical pharmacokinetic study demonstrated effective drug delivery and uptake into the arterial tissues at the therapeutic dose density (2.0 µg/mm²) with no evidence of drug toxicity demonstrated as follows: - Successful delivery of the device to the target treatment location without major procedural or device related complications, such as acute thrombosis, major bleeding, or flow-limiting dissection. - No morbidity or mortality device-related complications during the treatment procedures and in-life phases of the experiments. No major vessel abnormalities were reported. - Arterial paclitaxel concentrations were highest at the early time points and decreased to low but detectable through 60 days. Pharmacokinetic parameters of arterial tissue demonstrated a Cmax of 99.6 ng/mg. - Blood paclitaxel concentrations reached their maximum at 4 hours post-device deployment followed by a rapid elimination profile, reaching levels below quantification by 14 days post-procedure. - The presence of paclitaxel in major organs or muscles was not associated with any adverse clinical reactions. Systemic concentrations in non-target tissues exhibited much lower paclitaxel concentrations relative to the treated arteries at the earlier time points and further decreased to almost non-detectable levels over 60 days. Results indicate limited systemic and non-target tissue drug exposure to paclitaxel with treatment using Ranger DCB. Acute performance data demonstrated acceptable clinical safety (including no thrombus formation) and device performance. Pharmacokinetic data demonstrated localization of paclitaxel with limited systemic and non-target tissue exposure. Histopathology data demonstrated an acceptable drug dose and embolic load safety margin (3X safety margin) for the intended therapeutic dose of 2.0 µg/mm² and range of allowable balloon sizes. PMA P190019: FDA Summary of Safety and Effectiveness Data Page 15 of 51 {15} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 16 of 51 X. SUMMARY OF PRIMARY CLINICAL STUDY RANGER II SFA Trial The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of percutaneous balloon angioplasty with the Ranger Paclitaxel-Coated PTA Balloon Catheter (Ranger DCB), after pre-dilatation, of de novo and restenotic lesions in native superficial femoral and popliteal arteries with the Ranger DCB in the US, Canada, Europe (Austria and Belgium), Japan, and New Zealand under IDE # G160172. Data from this clinical study were the basis for the PMA approval decision. A summary of the pivotal study is presented below. A. Study Design Patients were treated between March 2, 2017 and August 30, 2018. The database for this PMA reflected data collected through November 19, 2019 and included 376 patients randomized 3:1 to the Ranger DCB (n=278) or the control PTA device (n=98). There were 67 enrolling investigational sites. The RANGER II SFA clinical study (NCT03064126) compares Ranger DCB vs. standard balloon angioplasty for the treatment of superficial femoral arteries (SFA) and proximal popliteal arteries (PPA). The RANGER II SFA study is a global, prospective, multi-center, single-blind, superiority, 3:1 (Ranger DCB vs. standard PTA) randomized controlled trial (RCT). It also includes a concurrent, non-blinded, non-randomized, single-arm, pharmacokinetic (PK) sub study and a concurrent, non-blinded, non-randomized, Long Balloon (LB) Sub Study. Data collected for the full cohort of 376 RCT subjects for study visits through November 19, 2019 is included in this summary. A subject was randomized once they had been consented, met eligibility criteria, and underwent successful pre-dilatation. 1. Clinical Inclusion and Exclusion Criteria Enrollment in the RANGER II SFA trial was limited to the following inclusion criteria: - Subject (or Legal Guardian) is willing and able to provide consent before any study-specific tests or procedures are performed and agree to attend all required follow-up visits; - Subject at least 20 years of age; - Chronic symptomatic lower limb ischemia defined as Rutherford classification 2, 3, or 4; - Target lesion is in the native SFA and/or PPA down to the P1 segment; - Patent popliteal and infrapopliteal arteries, i.e., single vessel runoff or better with at least one of three vessels patent (&lt;50% stenosis) to the ankle or foot; - Reference vessel diameter ≥ 4 mm and ≤ 8 mm by visual estimate (use of a {16} radiopaque ruler is recommended); and - Angiographic evidence that target lesion consists of a single de novo, non-stented and non-atherectomy treated or restenotic lesion (or tandem lesions or a combination lesion as defined below) that is: - ≥ 70% -99% stenotic with total lesion length up to 180 mm by visual estimate (use of a radiopaque ruler is recommended). - Occluded with total lesion length ≤ 100 mm by visual estimate (use of a radiopaque ruler is recommended). - If lesion is restenotic, most recent PTA treatment must be &gt; 3 months prior to enrollment. Notes: Combination lesions (a non-occlusive lesion that includes a totally occluded segment along its length) are eligible provided that the combined total lesion length is ≤180 mm. Tandem (or "adjacent") lesions may be enrolled providing they meet all of the following criteria: - Separated by a gap of ≤ 30 mm (3 cm); - Total combined lesion length meets requirements (angiographic inclusion criteria including 30 mm gap); - Able to be treated as a single lesion. Patients were not permitted to enroll into the RANGER II SFA trial if they meet any of the following exclusion criteria: - Life expectancy, documented in the Investigator’s opinion, of less than 12 months; - Hemorrhagic stroke or cardiac event (e.g. STEMI, unstable angina) within 6 months prior to enrollment; - Known allergies or sensitivities to heparin, aspirin, other anticoagulant/antiplatelet therapies, and/or paclitaxel; - Known hypersensitivity or contraindication to contrast dye that, in the opinion of the investigator, cannot be adequately pre-medicated; - Chronic renal insufficiency with serum creatinine &gt; 2.0 mg/dL within 30 days of index procedure or treatment with dialysis; - Platelet count &lt;80,000 mm³ or &gt;600,000 mm³ or history of bleeding diathesis; - Receiving immunosuppressive therapy; - Septicemia at the time of enrollment; - Any major (e.g., cardiac, peripheral, abdominal) intervention (including in the PMA P190019: FDA Summary of Safety and Effectiveness Data Page 17 of 51 {17} contralateral SFA/PPA) planned within 30 days post index procedure; - Presence of other hemodynamically significant outflow lesions in the target limb requiring intervention within 30 days of enrollment; - Failure to successfully cross the target lesion with a guidewire (successful crossing means tip of the crossing device is distal to the target lesion in the absence of flow-limiting dissections or perforations); - Failure to successfully pre-dilate the target vessel; - Patient has lesion that requires the use of adjunctive primary treatment modalities (i.e. laser, atherectomy, scoring/cutting balloon, other debulking devices, etc.) during the index procedure; - History of major amputation in the target limb; - Target lesion or vessel has ever been previously treated with stent (e.g. in-stent restenosis) or surgery. Target lesion or vessel has been treated with atherectomy or a DCB in the past 12 months; - Pregnant or breast feeding; - Presence of aneurysm in the target vessel; - Acute ischemia and/or acute thrombosis of the SFA/PPA prior to enrollment; - Patient has significant inflow disease which cannot be treated prior to the target lesion treatment; - Patient has perforated targeted vessel as evidenced by extravasation of contrast media; - Patient has severe calcification that renders the lesion undilatable; - Current participation in another investigational drug or device clinical trial that has not completed the primary endpoint at the time of randomization/enrollment or that clinically interferes with the current trial endpoints. Note: Studies requiring extended follow-up for products that were investigational, but have become commercially available since then are not considered investigational studies. ## 2. Follow-Up Schedule All patients are to be scheduled for evaluations at 1, 6, 12, 24, 36, 48, and 60 months. The 48 and 60 month visits can occur in office/clinic or by telephone. A subgroup of patients enrolled in a pharmacokinetics sub-study had blood drawn at 24 or 48 hours, 7, and 30 days post-procedure, as well as the required assessments through 60 months. Preoperatively, a screening was performed. A peri-procedure assessment was also performed. Table 9 below summarizes the objective parameters and key timepoints PMA P190019: FDA Summary of Safety and Effectiveness Data Page 18 of 51 {18} of the RANGER II SFA trial. PMA P190019: FDA Summary of Safety and Effectiveness Data Page 19 of 51 {19} Table 9: RANGER II SFA Data Collection Schedule | Procedure/Assessment | Pre-procedure [2] | During Index Procedure | Pre-Discharge | Day 1 or 2[6] | Day 7 (±1 day) | 1-month (30 ± 7 days) | 6-month (182 ± 30 days) | 12-month (365 ± 30 days) | 24-month (730 ± 30 days) | 36-month (1095 ± 30 days) | 48-month[5] (1460 ± 30 days) | 60-month[5] (1825 ± 30 days) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Informed Consent[1] | X | | | | | | | | | | | | | Confirm Inclusion/Exclusion | X | X | | | | | | | | | | | | Demographics and Medical History, Height and Weight | X | | | | | | | | | | | | | Pregnancy Test[2] | X | | | | | | | | | | | | | Physical Exam[3] | X | | X | | | X | X | X | X | X | | | | Complete Blood Count (CBC) and platelet count | X | | | | | | | | | | | | | Serum Creatinine | X | | | | | | | | | | | | | ABI Measurements | X | | | | | X | X | X | X | X | | | | Rutherford Classification | X | | | | | X | X | X | X | X | | | | Walking Impairment Questionnaire (WIQ) | X | | | | | X | X | X | X | X | | | | EQ-5D Questionnaire | X | | | | | X | X | X | X | X | | | | 6 Minute Walk Test (6MWT) | X | | | | | | X | X | | | | | | Angiogram[4] | | X | | | | | | | | | | | | Randomization/Enrollment | | X | | | | | | | | | | | | PK venous draw | X | X[6] | X | X | X | X | | | | | | | | Duplex Ultrasound[4] | | | | | | X | X | X | X | X | | | | Medication Assessment | X | X | X | | | X | X | X | X | X | X | X | | Adverse Events Assessment | | X | X | | | X | X | X | X[7] | X[7] | X[7] | X[7] | [1] Subject's consent obtained and informed consent form signed prior to obtaining any study-specific tests or procedures. Testing (CBC, platelets, ABI, and Rutherford Classification) completed as a part of the subject's standard of care, within 30 days of the index procedure and that meets the study (inclusion/exclusion) criteria, are not required to be repeated. [2] Performed within 30 days of procedure, except urine or blood pregnancy test required for females of childbearing potential performed within 24 hrs of procedure [3] Physical exam includes obtaining Vital signs (B/P, HR, RR*), Rutherford Classification and ABI at 1 mth, 6 mth, 12 mth, 24 mth and 36 mth follow up visits. Pre-discharge: Vital signs only. * Respiratory rate is not mandatory if not local standard of care. [4] Angiograms and Ultrasounds will be sent to the respective core lab for analysis. [5] The 48 month and 60 month visit may be conducted in the office/clinic or by telephone. [6] PK venous draw at screening, 10 min, 30 min, 1 hr, 3 hr, 6 hr, 24 or 48 hr after last Ranger DCB removal, Day 7 and Day 30 post index procedure. [7] Reporting required through the end of trial for SAEs, UADEs and ADEs/Device Deficiencies. AEs not related to the investigational device or procedure reported only through 12 month follow-up visit. PMA P190019: FDA Summary of Safety and Effectiveness Data {20} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 21 of 51 # 3. Clinical Endpoints Primary Safety Endpoint: The primary safety endpoint assessed the occurrence of Major Adverse Events (MAEs) defined as all causes of death through 1 month, target limb major amputation through 12 months and/or target lesion revascularization (TLR) through 12 months. This safety endpoint was designed to demonstrate that the 12-month MAE-free rate for the Ranger DCB treatment group is non-inferior to the Standard PTA control group. Primary Effectiveness Endpoint: The RCT primary effectiveness endpoint assessed primary patency at 12 months post-procedure. This effectiveness endpoint was designed to demonstrate that the 12-month primary patency for the Ranger DCB treatment group is superior to the Standard PTA control group. Primary vessel patency was defined as the percentage of lesions (target stented segments) that reached the endpoint without a hemodynamically significant stenosis on duplex ultrasound (DUS) (Peak Systolic Velocity Ratio {PSVR} is ≤ 2.4), and without clinically-driven TLR or bypass of the target lesion before or on the DUS follow up visit. Secondary Endpoints: The secondary endpoints that will be evaluated, but are not necessarily powered to make statistically based conclusions, for the RANGER II SFA study are listed below: - Technical success defined as successful delivery, balloon inflation and deflation and retrieval of the intact trial device without burst below the rated burst pressure (RBP) - Procedural success defined as residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by core laboratory evaluation (if core laboratory assessment is not available then the site-reported estimate is used) - Clinical success defined as procedural success without procedural complications (i.e. death, major target limb amputation, thrombosis of the target lesion, or clinically-driven TLR) prior to discharge - Major Adverse Events (MAE) through 60 months. MAEs are defined as all-cause death post-index procedure, TLR, and major target limb amputation - Death of any cause within 30 days, 6, 12, 24, 36, 48 and 60 months - TVR rates at 6, 12, 24, 36, 48 and 60 months - TLR rates at 6, 12, 24, 36, 48 and 60 months - Rate of Primary and Secondary sustained clinical improvement as assessed by changes in Rutherford Classification from baseline at 1, 6, 12, 24 and 36 months post-procedure - Rate of Hemodynamic Improvement as assessed by changes in Ankle-Brachial Index (ABI) from baseline at 1, 6, 12, 24 and 36 months post- {21} procedure - Duplex-defined binary restenosis (PSVR &gt; 2.4) of the target lesion at 1, 6, 12, 24 and 36 months - Walking Improvement (distance) at 6 months and 12 months as assessed by changes in the Six Minute Hall Walk Test (6MWT) from baseline - Walking Improvement and Patient Utility Values assessed at 1, 6, 12, 24 and 36 months as assessed by change in Walking Impairment Questionnaire (WIQ) and EQ-5D™ from baseline - Changes in healthcare utilization over time - PK parameters calculated for subjects in the PK substudy ## B. Accountability of Full PMA Cohort Sixty-seven (67) centers located in the United States, Japan, New Zealand, Europe (Belgium and Austria) and Canada recruited 376 RCT subjects requiring treatment of lesions in the femoropopliteal arteries. Fifty-eight (58%) percent of all subjects were enrolled in the United States (56% in the RCT, 100% in the PK sub-study). As of the database snapshot on November 19, 2019, a total of 343 RCT subjects completed the 12-month follow-up visit as required by the RANGER II SFA protocol. Table 10 displays the subject disposition at each follow-up visit for the RCT. Table 10: Subject Disposition Through 12 Months – RCT, Intent-to-Treat (N=376) | | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | Overall (N=376 Subjects) | | --- | --- | --- | --- | | Intent to Treat (All Enrolled Subjects) | 278 | 98 | 376 | | | | | | | Eligible for 1-Month Clinical Follow-up | 277 | 98 | 375 | | Not Eligible for 1-Month Clinical Follow-up | 1 | 0 | 1 | | Death ≤ 37 Days with no 1-Month Clinical Follow-up Performed | 1 | 0 | 1 | | Withdrawal | 0 | 0 | 0 | | Adverse Event | 0 | 0 | 0 | | Investigator Discretion | 0 | 0 | 0 | | Lost to Follow-up | 0 | 0 | 0 | | Withdrew Consent | 0 | 0 | 0 | | Failed Angioplasty attempt | 0 | 0 | 0 | | Other | 0 | 0 | 0 | | 1-Month Visit Missed | 5 | 1 | 6 | | 1-Month Visit Window Not Open | 0 | 0 | 0 | | 1-Month Visit Window Still Open | 0 | 0 | 0 | | 1-Month Visit Pending Data Entry | 0 | 0 | 0 | | 1-Month Clinical Follow-up Performed | 272 | 97 | 369 | | 1-Month Clinical Follow-up or Death (Evaluable) | 273 | 97 | 370 | PMA P190019: FDA Summary of Safety and Effectiveness Data Page 22 of 51 {22} | | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | Overall (N=376 Subjects) | | --- | --- | --- | --- | | 1-Month Clinical Follow-up Compliance1 | 98.2% (272/277) | 99.0% (97/98) | 98.4% (369/375) | | 1-Month Duplex Ultrasound Follow-up Compliance1,2 | 96.4% (267/277) | 98.0% (96/98) | 96.8% (363/375) | | Eligible for 6-Month Clinical Follow-up | 272 | 93 | 365 | | Not Eligible for 6-Month Clinical Follow-up | 6 | 5 | 11 | | Death ≤ 212 Days with no 6-Month Clinical Follow- up Performed | 3 | 2 | 5 | | Withdrawal | 3 | 3 | 6 | | Adverse Event | 0 | 0 | 0 | | Investigator Discretion | 0 | 0 | 0 | | Lost to Follow-up | 0 | 0 | 0 | | Withdrew Consent | 3 | 3 | 6 | | Failed Angioplasty attempt | 0 | 0 | 0 | | Other | 0 | 0 | 0 | | 6-Month Visit Missed | 9 | 2 | 11 | | 6-Month Visit Window Not Open | 0 | 0 | 0 | | 6-Month Visit Window Still Open | 0 | 0 | 0 | | 6-Month Visit Pending Data Entry | 0 | 0 | 0 | | 6-Month Clinical Follow-up Performed | 263 | 91 | 354 | | 6-Month Clinical Follow-up or Death (Evaluable) | 266 | 93 | 359 | | 6-Month Clinical Follow-up Compliance1 | 95.6% (263/275) | 94.8% (91/96) | 95.4% (354/371) | | 6-Month Duplex Ultrasound Follow-up Compliance1,2 | 94.9% (261/275) | 93.8% (90/96) | 94.6% (351/371) | | Eligible for 12-Month Clinical Follow-up | 263 | 92 | 355 | | Not Eligible for 12-Month Clinical Follow-up | 15 | 6 | 21 | | Death ≤ 395 Days with no 12-Month Clinical Follow-up Performed | 6 | 2 | 8 | | Withdrawal | 9 | 4 | 13 | | Adverse Event | 0 | 0 | 0 | | Investigator Discretion | 1 | 0 | 1 | | Lost to Follow-up | 0 | 0 | 0 | | Withdrew Consent | 7 | 4 | 11 | | Failed Angioplasty attempt | 0 | 0 | 0 | | Other | 1 | 0 | 1 | | 12-Month Visit Missed | 11 | 1 | 12 | | 12-Month Visit Window Not Open | 0 | 0 | 0 | | 12-Month Visit Window Still Open | 0 | 0 | 0 | | 12-Month Visit Pending Data Entry | 0 | 0 | 0 | | 12-Month Clinical Follow-up Performed | 252 | 91 | 343 | | 12-Month Clinical Follow-up or Death (Evaluable) | 258 | 93 | 351 | | 12-Month Clinical Follow-up Compliance1 | 92.6% (252/272) | 94.8% (91/96) | 93.2% (343/368) | | 12-Month Duplex Ultrasound Follow-up Compliance1,2 | 92.3% (251/272) | 93.8% (90/96) | 92.7% (341/368) | | 1 Death prior to the visit window or within the visit window with no clinical follow-up does not contribute to the denominators and numerators of the compliance rate. 2 All site-reported duplex ultrasounds apply, including anyone without interpretable images. | | | | PMA P190019: FDA Summary of Safety and Effectiveness Data {23} # C. Study Population Demographics and Baseline Characteristics # Patient Population Table 11 provides a summary of baseline demographics and medical history for subjects enrolled into the RANGER II SFA Randomized Controlled Trial (RCT). Table 11: Baseline Demographics and Medical History - RCT (N=376) | Subject Characteristic | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | | --- | --- | --- | | Demographics | | | | Age (Year) | 70.6 ± 9.5 (278) (43.0, 89.0) | 69.1 ± 10.3 (98) (47.0, 88.0) | | Gender | | | | Male | 62.2% (173/278) | 68.4% (67/98) | | Female | 37.8% (105/278) | 31.6% (31/98) | | Intersex | 0.0% (0/278) | 0.0% (0/98) | | Unknown | 0.0% (0/278) | 0.0% (0/98) | | Race/Ethnicity | | | | Hispanic or Latino | 7.6% (21/278) | 8.2% (8/98) | | Caucasian | 55.8% (155/278) | 60.2% (59/98) | | Asian | 27.7% (77/278) | 25.5% (25/98) | | Japanese | 27.7% (77/278) | 25.5% (25/98) | | Chinese | 0.0% (0/278) | 0.0% (0/98) | | Korean | 0.0% (0/278) | 0.0% (0/98) | | Other Asian | 0.0% (0/278) | 0.0% (0/98) | | Black, or African heritage | 7.2% (20/278) | 4.1% (4/98) | | Native Hawaiian or other Pacific Islander | 0.0% (0/278) | 0.0% (0/98) | | American Indian or Alaska Native | 0.4% (1/278) | 0.0% (0/98) | | Other | 0.4% (1/278) | 0.0% (0/98) | | Not Disclosed | 1.1% (3/278) | 2.0% (2/98) | | General Medical History | | | | History of Smoking | | | | Current | 31.3% (87/278) | 45.9% (45/98) | | Previous | 54.0% (150/278) | 38.8% (38/98) | | Never | 14.4% (40/278) | 15.3% (15/98) | | Unknown | 0.4% (1/278) | 0.0% (0/98) | | Current Diabetes Mellitus | 42.4% (118/278) | 43.9% (43/98) | | Type 1 | 1.7% (2/118) | 0.0% (0/43) | | Type 2 | 96.6% (114/118) | 100.0% (43/43) | | Unknown | 1.7% (2/118) | 0.0% (0/43) | | Current Method of Treatment | | | | Diet | 26.3% (31/118) | 27.9% (12/43) | | Diet(only) | 5.1% (6/118) | 11.6% (5/43) | | Medically Treated | 94.1% (111/118) | 88.4% (38/43) | | Oral Agent | 73.7% (87/118) | 74.4% (32/43) | | Insulin | 36.4% (43/118) | 39.5% (17/43) | | Other | 1.7% (2/118) | 0.0% (0/43) | PMA P190019: FDA Summary of Safety and Effectiveness Data {24} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 25 of 51 | Subject Characteristic | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | | --- | --- | --- | | Unknown | 0.8% (1/118) | 0.0% (0/43) | | History of Hyperlipidemia requiring medication | 75.9% (211/278) | 79.6% (78/98) | | History of Hypertension requiring medication | 90.3% (251/278) | 81.6% (80/98) | | History of Chronic Obstructive Pulmonary Disease | 18.9% (52/275) | 21.4% (21/98) | | Cardiac History | | | | History of Coronary Artery Disease | 47.5% (131/276) | 44.9% (44/98) | | History of Myocardial Infarction (MI) | 16.6% (46/277) | 14.4% (14/97) | | History of Congestive Heart Failure | 9.4% (26/277) | 9.2% (9/98) | | New York Heart Assoc. (NYHA) Classification | | | | I | 38.5% (10/26) | 0.0% (0/9) | | II | 23.1% (6/26) | 66.7% (6/9) | | III | 3.8% (1/26) | 0.0% (0/9) | | IV | 0.0% (0/26) | 0.0% (0/9) | | Unknown | 34.6% (9/26) | 33.3% (3/9) | | History of Percutaneous Coronary Intervention (PCI) | 29.6% (81/274) | 34.7% (34/98) | | History of Coronary Artery Bypass Graft (CABG) Surgery | 12.6% (35/277) | 15.5% (15/97) | | Current Anginal Status | | | | Stable Angina | 12.6% (35/278) | 13.3% (13/98) | | Unstable Angina | 0.4% (1/278) | 0.0% (0/98) | | None | 87.1% (242/278) | 86.7% (85/98) | | Unknown | 0.0% (0/278) | 0.0% (0/98) | | Neurologic/Renal History | | | | History of Transient Ischemic Attacks (TIA) | 5.1% (14/275) | 7.2% (7/97) | | History of Cerebrovascular Accident (CVA) | 13.0% (36/276) | 11.2% (11/98) | | History of Renal Insufficiency | 10.8% (30/278) | 5.2% (5/97) | | History of Renal Percutaneous Intervention | 2.2% (6/275) | 1.0% (1/97) | | ABI (mmHg ratio) | 0.8 ± 0.2 (276) (0.3, 1.7) | 0.8 ± 0.2 (93) (0.2, 1.5) | | Rutherford Category | | | | 2 | 39.2% (109/278) | 33.7% (33/98) | | 3 | 51.4% (143/278) | 59.2% (58/98) | | 4 | 9.4% (26/278) | 7.1% (7/98) | {25} # Lesion Characteristics Baseline lesion characteristics, procedural characteristics, and post-procedure measurements for the RCT are summarized in Table 12 Table 12: Baseline, Procedure and Post-procedure Reported Lesion Characteristics - RCT (N=376) | | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | | --- | --- | --- | | Baseline Angiographic Core Lab Reported Lesion Characteristics | | | | Treated Limb | | | | Right leg | 48.9% (136/278) | 53.1% (52/98) | | Left leg | 51.1% (142/278) | 46.9% (46/98) | | Lesion Location | | | | pSFA | 17.3% (48/278) | 18.4% (18/98) | | mSFA | 52.5% (146/278) | 44.9% (44/98) | | dSFA | 24.8% (69/278) | 32.7% (32/98) | | pPopliteal | 4.3% (12/278) | 4.1% (4/98) | | mPopliteal | 1.1% (3/278) | 0.0% (0/98) | | dPopliteal | 0.0% (0/278) | 0.0% (0/98) | | Not Available | 0.0% (0/278) | 0.0% (0/98) | | Lesion Length (mm) | 82.5 ± 48.9 (278) (9.2, 232.5) | 79.9 ± 49.3 (98) (13.6, 232.1) | | Lesion Type | | | | Eccentric Lesion | 77.0% (214/278) | 74.5% (73/98) | | Concentric Lesion | 23.0% (64/278) | 25.5% (25/98) | | Not Available | 0.0% (0/278) | 0.0% (0/98) | | Thrombus | | | | None | 97.8% (272/278) | 99.0% (97/98) | | Possible | 0.0% (0/278) | 1.0% (1/98) | | Small | 0.0% (0/278) | 0.0% (0/98) | | Moderate | 0.0% (0/278) | 0.0% (0/98) | | Large | 0.4% (1/278) | 0.0% (0/98) | | Total occlusion | 0.4% (1/278) | 0.0% (0/98) | | Not Available | 1.4% (4/278) | 0.0% (0/98) | | PACSS Calcification | | | | Grade 0 | 35.3% (98/278) | 22.4% (22/98) | | Grade 1 | 12.6% (35/278) | 14.3% (14/98) | | Grade 2 | 2.5% (7/278) | 1.0% (1/98) | | Grade 3 | 36.3% (101/278) | 52.0% (51/98) | | Grade 4 | 11.5% (32/278) | 10.2% (10/98) | | NA | 1.8% (5/278) | 0.0% (0/98) | | Ulceration (Present) | 4.3% (12/278) | 3.1% (3/98) | | Aneurysm (Present) | 0.7% (2/278) | 3.1% (3/98) | | TIMI Flow | | | | Grade 0 | 16.9% (47/278) | 23.5% (23/98) | | Grade 1 | 1.8% (5/278) | 2.0% (2/98) | | Grade 2 | 0.7% (2/278) | 0.0% (0/98) | | Grade 3 | 67.6% (188/278) | 63.3% (62/98) | PMA P190019: FDA Summary of Safety and Effectiveness Data {26} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 27 of 51 | | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | | --- | --- | --- | | Not Available | 12.9% (36/278) | 11.2% (11/98) | | TASC II Type | | | | A | 59.4% (165/278) | 61.2% (60/98) | | B | 30.2% (84/278) | 30.6% (30/98) | | C | 9.0% (25/278) | 6.1% (6/98) | | D | 1.4% (4/278) | 2.0% (2/98) | | Not Available | 0.0% (0/278) | 0.0% (0/98) | | Minimum Lumen Diameter (MLD, mm) | 1.4 ± 0.9 (278) (0.0, 4.5) | 1.2 ± 1.1 (98) (0.0, 4.3) | | Reference Vessel Diameter (RVD, mm) | 5.1 ± 0.9 (278) (3.0, 8.7) | 5.1 ± 0.9 (98) (3.2, 8.3) | | % Diameter Stenosis | 73.7 ± 16.9 (278) (26.1, 100.0) | 78.2 ± 18.4 (98) (35.8, 100.0) | | 100% (Occlusion) | 18.3% (51/278) | 29.6% (29/98) | | Angiographic Core Lab Reported Post-Procedure Measurements | | | | Dissection | | | | None | 24.5% (68/278) | 35.7% (35/98) | | Grade A | 0.0% (0/278) | 0.0% (0/98) | | Grade B | 45.3% (126/278) | 37.8% (37/98) | | Grade C | 16.5% (46/278) | 16.3% (16/98) | | Grade D | 12.9% (36/278) | 5.1% (5/98) | | Grade E | 0.0% (0/278) | 0.0% (0/98) | | Grade F | 0.0% (0/278) | 0.0% (0/98) | | Not Available | 0.7% (2/278) | 5.1% (5/98) | | In-Segment Percent Diameter Stenosis (% DS) | 25.0 ± 12.2 (277) (-7.5, 61.7) | 24.5 ± 12.9 (93) (-12.1, 59.1) | | In-Segment Minimum Lumen Diameter (MLD, mm) | 3.8 ± 0.7 (277) (1.8, 5.8) | 3.8 ± 0.8 (93) (2.1, 6.5) | | Procedural Characteristics | | | | Pre-dilatation^{a} | | | | Pre-dilatation Performed | 100.0% (278/278) | 100.0% (98/98) | | Post-dilatation^{a} | | | | Post-dilatation Performed | 13.3% (37/278) | 21.4% (21/98) | | Bare Metal Stent bailout^{a} | 5.0% (14/278) | 9.2% (9/98)^{b} | | Technical Success^{1a} | 99.6% (277/278) | NA | | Procedural Success^{2} | 96.8% (269/278) | 99.0% (97/98) | | Clinical Success^{3} | 96.0% (267/278) | 98.0% (96/98) | | Sites may report more than one lesion location. a Site reported data. b One Standard PTA subject received a bailout drug-eluting stent not allowed per protocol. 1 Technical Success: successful delivery, balloon inflation and deflation and retrieval of the intact trial device without burst below the rated burst pressure (RBP). Device deficiency data was collected only for Ranger DCB. 2 Procedural Success: residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by core laboratory evaluation (if core laboratory assessment is not available then the site-reported estimate is used). 3 Clinical Success: procedural success without procedural complications (i.e. death, major target limb amputation, thrombosis of the target lesion, or clinically-driven TLR) prior to discharge. | | | {27} # D. Safety and Effectiveness Results # 1. Primary Safety Results - RCT Primary results for the full RCT cohort are presented below. Ranger DCB will be concluded to be non-inferior to Standard PTA regarding the primary safety endpoint, 12-month MAE-free rate, if the one-sided lower $97.5\%$ confidence bound on the difference between treatment groups (Ranger DCB vs. Standard PTA) in 12- month MAE-free rate is greater than -0.1 (or $-10\%$ ). Based on the intent-to-treat (ITT) population, the MAE-free rate at 12 months was $94.1\%$ (241/256) in the Ranger DCB group and $83.5\%$ (76/91) in the Standard PTA group respectively, with the one-sided lower $97.5\%$ confidence bound on the difference to be $2.48\%$ (non-inferiority p-value $&lt; .0001$ ). The primary safety endpoint was also evaluated based on the Per-Protocol (PP) cohort which consisted of randomized subjects who met the eligibility criteria and received the assigned treatment, and had similar results to the ITT analysis. Therefore, the primary safety endpoint was met and Ranger DCB is concluded to be non-inferior to Standard PTA for the primary safety endpoint. The primary safety results for this study are presented below in Table 13. Kaplan-Meier plot of freedom from MAE through 365 days is presented in Figure 4. Table 13: Primary Safety Endpoint - Full Cohort RCT, Intent-to-Treat (N=376), Per Protocol (N=370) | Intent-To-Treat (N=376) | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | Difference [95% CI] | One-sided 97.5% Lower CI | P-value2 | | --- | --- | --- | --- | --- | --- | | 12-Month MAE1-Free | 94.1% (241/256) | 83.5% (76/91) | 10.6% [2.5%, 18.8%] | 2.48% | <.0001 | | Per-Protocol (N=370) | Ranger DCB (N=274 Subjects) | Standard PTA (N=96 Subjects) | Difference [95% CI] | One-sided 97.5% Lower CI | P-value2 | | 12-Month MAE1-Free | 94.8% (239/252) | 84.3% (75/89) | 10.6% [2.5%, 18.6%] | 2.53% | <.0001 | | 1 Primary Safety: Twelve-Month Major Adverse Events (MAEs) defined as all causes of death through 1 month, target limb major amputation through 12 months and/or target lesion revascularization through 12 months.2 P-value is adjusted for non-inferiority margin (-10%).Note:The success criteria for 12M safety endpoint hypothesis is the one-sided 97.5% lower bound greater than non-inferiority margin (i.e.>10%).The success criteria for 12M effectiveness endpoint hypothesis is the one-sided 97.5% lower bound greater than zero (i.e.>0).All events were adjudicated by the independent Clinical Events Committee and all DUS and angiographic measurements were made by the independent core laboratories. | | | | | | PMA P190019: FDA Summary of Safety and Effectiveness Data {28} ![img-3.jpeg](img-3.jpeg) | | Time from Index Procedure (Days) | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Number of Subjects with Ranger DCB Balloon | 0 | 1-30 | 31-60 | 61-90 | 91-120 | 121-182 | 183-270 | 271-365 | | Entered | 278 | 277 | 276 | 274 | 274 | 271 | 269 | 255 | | Censored | 1 | 0 | 2 | 0 | 2 | 1 | 11 | 41 | | Events | 0 | 1 | 0 | 0 | 1 | 1 | 3 | 9 | | Event Rate | 0% | 0.4% | 0.4% | 0.4% | 0.7% | 1.1% | 2.2% | 5.9% | | Event Free | 100% | 99.6% | 99.6% | 99.6% | 99.3% | 98.9% | 97.8% | 94.1% | | Std Error | 0% | 0.4% | 0.4% | 0.4% | 0.5% | 0.6% | 0.9% | 1.5% | | Number of Subjects with Standard PTA Balloon | 0 | 1-30 | 31-60 | 61-90 | 91-120 | 121-182 | 183-270 | 271-365 | | Entered | 98 | 98 | 98 | 96 | 96 | 94 | 91 | 83 | | Censored | 0 | 0 | 1 | 0 | 1 | 2 | 2 | 11 | | Events | 0 | 0 | 1 | 0 | 1 | 1 | 6 | 6 | | Event Rate | 0% | 0% | 1.0% | 1.0% | 2.1% | 3.1% | 9.6% | 16.4% | | Event Free | 100% | 100% | 99.0% | 99.0% | 97.9% | 96.9% | 90.4% | 83.6% | | Std Error | 0% | 0% | 1.0% | 1.0% | 1.4% | 1.8% | 3.0% | 3.9% | Subjects event-free at 365 days or later are censored at greater than 365 days. Event rate and standard error estimates are for interval end. Standard errors by Greenwood formula. Figure 4: Kaplan-Meier Plot – Freedom from Major Adverse Event Through 12 Months, Intent-to-Treat (N=376 Subjects) PMA P190019: FDA Summary of Safety and Effectiveness Data {29} Table 14 shows the individual components of the primary safety endpoint: all causes of death through 1 month, target limb major amputation through 12 months and target lesion revascularization (TLR) through 12 months for the full RCT cohort. Table 14: Safety Endpoints through 12 Months – Full Cohort RCT, Intent-to-Treat (N=376) | | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | Difference [95% CI] | | --- | --- | --- | --- | | Primary Safety Endpoint | | | | | 12-Month MAE1-Free | 94.1% (241/256) | 83.5% (76/91) | 10.6% [2.5%, 18.8%] | | 12-Month MAE1 and Components | | | | | 12-Month MAE1 (Composite Endpoint) | 5.9% (15/256) | 16.5% (15/91) | | | All Causes of Deaths at 1 Month | 0.4% (1/256) | 0.0% (0/91) | | | Target Limb Major Amputation | 0.0% (0/256) | 0.0% (0/91) | | | Target Lesion Revascularization | 5.5% (14/256) | 16.5% (15/91) | | | Clinically-Driven | 5.5% (14/256) | 16.5% (15/91) | | | Non-Clinically-Driven | 0.0% (0/256) | 0.0% (0/78) | | | 1Twelve-Month Major Adverse Events (MAEs) defined as all causes of death through 1 month, target limb major amputation through 12 months and/or target lesion revascularization through 12 months | | | | Table 15 displays the frequency of Serious Adverse Events (SAE) by MedDRA System/Organ Class that were reported as of the data snapshot date of November 19, 2019, observed in the RANGER II SFA pivotal trial for the full RCT cohort. A serious adverse event is defined as an event that led to death or led to a serious deterioration in the health of the subject; resulted in a life-threatening illness or injury; resulted in a permanent impairment of a body structure or a body function; required in-subject hospitalization or prolongation of existing hospitalization; or resulted in medical or surgical intervention to prevent permanent impairment to body structure or a body function. Table 15: Frequency of Site-Reported Serious Adverse Events to 12 Months – Full Cohort - Intent-to-Treat (N=376 Subjects) | Serious Adverse Event | | Ranger DCB (N=278 Subjects) | | Standard PTA (N=98 Subjects) | | | --- | --- | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | Total | Total | 228 | 45.7% (127/278) | 94 | 48.0% (47/98) | | Vascular disorders | Total | 87 | 21.2% (59/278) | 36 | 27.6% (27/98) | | | Peripheral artery stenosis | 36 | 10.4% (29/278) | 19 | 14.3% (14/98) | | | Intermittent claudication | 19 | 6.1% (17/278) | 6 | 5.1% (5/98) | | | Peripheral artery occlusion | 11 | 2.9% (8/278) | 4 | 4.1% (4/98) | | | Peripheral arterial occlusive disease | 9 | 2.2% (6/278) | 2 | 1.0% (1/98) | PMA P190019: FDA Summary of Safety and Effectiveness Data {30} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 31 of 51 | Serious Adverse Event | | Ranger DCB (N=278 Subjects) | | Standard PTA (N=98 Subjects) | | | --- | --- | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | | Peripheral ischemia | 3 | 1.1% (3/278) | 0 | 0.0% (0/98) | | | Hematoma | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Hypotension | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Peripheral vascular disorder | 1 | 0.4% (1/278) | 1 | 1.0% (1/98) | | | Essential hypertension | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Lower limb artery perforation | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Peripheral coldness | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Thrombophlebitis superficial | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Deep vein thrombosis | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Hypertensive crisis | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Orthostatic hypotension | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Peripheral embolism | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Cardiac disorders | Total | 30 | 7.6% (21/278) | 14 | 8.2% (8/98) | | | Atrial fibrillation | 4 | 1.1% (3/278) | 1 | 1.0% (1/98) | | | Cardiac failure congestive | 4 | 1.1% (3/278) | 1 | 1.0% (1/98) | | | Angina pectoris | 4 | 1.4% (4/278) | 0 | 0.0% (0/98) | | | Coronary artery disease | 3 | 1.1% (3/278) | 5 | 3.1% (3/98) | | | Angina unstable | 3 | 1.1% (3/278) | 2 | 2.0% (2/98) | | | Coronary artery stenosis | 3 | 1.1% (3/278) | 1 | 1.0% (1/98) | | | Acute myocardial infarction | 2 | 0.7% (2/278) | 1 | 1.0% (1/98) | | | Cardiac arrest | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Cardiac failure | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Cardiac failure acute | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Coronary artery occlusion | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Ischemic cardiomyopathy | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Myocardial infarction | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Ventricular tachycardia | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Aortic valve incompetence | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Atrioventricular block | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Mitral valve incompetence | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Injury, poisoning and procedural complications | Total | 20 | 6.8% (19/278) | 10 | 7.1% (7/98) | | | Vascular procedure complication | 11 | 4.0% (11/278) | 4 | 4.1% (4/98) | | | Vascular pseudoaneurysm | 4 | 1.4% (4/278) | 1 | 1.0% (1/98) | | | Anemia postoperative | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Contusion | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Extradural hematoma | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Peripheral artery bypass graft stenosis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Subdural hematoma | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | {31} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 32 of 51 | Serious Adverse Event | | Ranger DCB (N=278 Subjects) | | Standard PTA (N=98 Subjects) | | | --- | --- | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | | Ankle fracture | 0 | 0.0% (0/278) | 2 | 1.0% (1/98) | | | Humerus fracture | 0 | 0.0% (0/278) | 2 | 1.0% (1/98) | | | Cervical vertebral fracture | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Infections and infestations | Total | 17 | 6.1% (17/278) | 6 | 5.1% (5/98) | | | Pneumonia | 4 | 1.4% (4/278) | 2 | 2.0% (2/98) | | | Cellulitis | 2 | 0.7% (2/278) | 1 | 1.0% (1/98) | | | Diverticulitis | 2 | 0.7% (2/278) | 1 | 1.0% (1/98) | | | Post procedural infection | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Bronchitis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Bronchopulmonary aspergillosis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Cystitis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Device related infection | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Enteritis infectious | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Sepsis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Urinary tract infection | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Osteomyelitis | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Pyelonephritis | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | General disorders and administration site conditions | Total | 12 | 4.0% (11/278) | 1 | 1.0% (1/98) | | | Catheter site hematoma | 5 | 1.4% (4/278) | 0 | 0.0% (0/98) | | | Non-cardiac chest pain | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Accidental death | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Chest pain | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Device related thrombosis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Implant site inflammation | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Oedema peripheral | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Death | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Respiratory, thoracic and mediastinal disorders | Total | 11 | 3.2% (9/278) | 4 | 4.1% (4/98) | | | Acute respiratory failure | 3 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Respiratory failure | 2 | 0.7% (2/278) | 2 | 2.0% (2/98) | | | Chronic obstructive pulmonary disease | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Dyspnea | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Hemothorax | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Pleural effusion | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Pulmonary embolism | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Pneumothorax | 0 | 0.0% (0/278) | 2 | 2.0% (2/98) | | Gastrointestinal | Total | 9 | 3.2% (9/278) | 5 | 4.1% (4/98) | {32} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 33 of 51 | Serious Adverse Event | | Ranger DCB (N=278 Subjects) | | Standard PTA (N=98 Subjects) | | | --- | --- | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | disorders | | | | | | | | Constipation | 1 | 0.4% (1/278) | 1 | 1.0% (1/98) | | | Abdominal pain upper | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Diarrhea | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Enteritis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Gastrointestinal hemorrhage | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Large intestinal stenosis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Lower gastrointestinal hemorrhage | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Retroperitoneal hematoma | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Upper gastrointestinal hemorrhage | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Inguinal hernia | 0 | 0.0% (0/278) | 3 | 3.1% (3/98) | | | Pancreatitis acute | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Renal and urinary disorders | Total | 8 | 2.5% (7/278) | 6 | 3.1% (3/98) | | | Acute kidney injury | 3 | 1.1% (3/278) | 4 | 2.0% (2/98) | | | Renal failure | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Haematuria | 1 | 0.4% (1/278) | 1 | 1.0% (1/98) | | | Calculus urinary | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Urinary bladder polyp | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Urinary retention | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Musculoskeletal and connective tissue disorders | Total | 7 | 2.5% (7/278) | 4 | 4.1% (4/98) | | | Back pain | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Pain in extremity | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Osteoarthritis | 1 | 0.4% (1/278) | 2 | 2.0% (2/98) | | | Intervertebral disc protrusion | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Myalgia | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Cervical spinal stenosis | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Plantar fasciitis | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Total | 7 | 2.5% (7/278) | 1 | 1.0% (1/98) | | | Benign lung neoplasm | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Invasive ductal breast carcinoma | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Lung neoplasm malignant | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Malignant neoplasm of renal pelvis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Prostate cancer | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Squamous cell carcinoma of | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | {33} PMA P190019: FDA Summary of Safety and Effectiveness Data Page 34 of 51 | Serious Adverse Event | | Ranger DCB (N=278 Subjects) | | Standard PTA (N=98 Subjects) | | | --- | --- | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | | lung | | | | | | | Transitional cell carcinoma | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Bladder cancer | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Nervous system disorders | Total | 7 | 2.2% (6/278) | 0 | 0.0% (0/98) | | | Cerebral infarction | 2 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Cerebrovascular accident | 2 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Dementia with Lewy bodies | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Headache | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Syncope | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | Blood and lymphatic system disorders | Total | 3 | 1.1% (3/278) | 1 | 1.0% (1/98) | | | Anemia | 2 | 0.7% (2/278) | 1 | 1.0% (1/98) | | | Iron deficiency anemia | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | Metabolism and nutrition disorders | Total | 3 | 0.7% (2/278) | 0 | 0.0% (0/98) | | | Decreased appetite | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Hyperglycemia | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Hyponatraemia | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | Skin and subcutaneous tissue disorders | Total | 2 | 0.7% (2/278) | 3 | 2.0% (2/98) | | | Skin ulcer | 2 | 0.7% (2/278) | 1 | 1.0% (1/98) | | | Diabetic foot | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Drug eruption | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Eye disorders | Total | 1 | 0.4% (1/278) | 1 | 1.0% (1/98) | | | Cataract | 1 | 0.4% (1/278) | 1 | 1.0% (1/98) | | Psychiatric disorders | Total | 1 | 0.4% (1/278) | 1 | 1.0% (1/98) | | | Delirium | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Mental status changes | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | Ear and labyrinth disorders | Total | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Vertigo | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | Hepatobiliary disorders | Total | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Cholelithiasis | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | Reproductive system and breast disorders | Total | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | | Uterine polyp | 1 | 0.4% (1/278) | 0 | 0.0% (0/98) | | Investigations | Total | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | | | Hemoglobin decreased | 0 | 0.0% (0/278) | 1 | 1.0% (1/98) | {34} | Serious Adverse Event | | Ranger DCB (N=278 Subjects) | | Standard PTA (N=98 Subjects) | | | --- | --- | --- | --- | --- | --- | | MedDRA System Organ Class | MedDRA Preferred Term | Events | Rate of Subjects with Event | Events | Rate of Subjects with Event | | "Events" numbers are total episodes of each type of event among all subjects. "Rate of Subjects with Event" numbers are percent of subjects who experienced one or more episodes of the event. "Events" numbers for "TOTAL" are the sum of the individual event category totals. "Rate of Subjects with Event" numbers for "TOTAL" is the percent of subjects who experienced an adverse event. | | | | | | # 2. Primary Effectiveness Results - RCT Primary effectiveness results for the full RCT cohort are presented in the section below. Based on the ITT population, primary patency at 12 months was $82.9\%$ (194/234) in the Ranger DCB group and $66.3\%$ (57/86) in the Standard PTA group respectively, with the one-sided lower $97.5\%$ confidence bound on the difference to be $5.53\%$ (p-value $= 0.0017$ ). The primary effectiveness endpoint was also evaluated based on the PP population and had similar results. Therefore, the primary effectiveness endpoint was met and the Ranger DCB is concluded to be superior to Standard PTA for the primary effectiveness endpoint. Primary effectiveness results for the full cohort are provided in Table 16. Kaplan-Meier plot of primary patency through 13 months is presented in Figure 5. Table 16: Primary Patency Endpoint through 12 Months – Full Cohort RCT, Intent-to-Treat (N=376), Per Protocol (N=370) | Intent-To-Treat (N=376) | Ranger DCB (N=278 Subjects) | Standard PTA (N=98 Subjects) | Difference [95% CI] | One-sided 97.5% Lower CI | P-value | | --- | --- | --- | --- | --- | --- | | 12-Month Primary Patency1 | 82.9% (194/234) | 66.3% (57/86) | 16.6% [5.5%, 27.7%] | 5.53% | 0.0017 | | Per-Protocol (N=370) | Ranger DCB (N=274 Subjects) | Standard PTA (N=96 Subjects) | Difference [95% CI] | One-sided 97.5% Lower CI | P-value | | 12-Month Primary Patency1 | 83.1% (192/231) | 66.7% (56/84) | 16.5% [5.3%, 27.6%] | 5.27% | 0.0020 | | 1 Primary Patency: percentage (%) of lesions (target lesion segments) that reach endpoint without a hemodynamically significant stenosis on DUS and without clinically-driven TLR or, bypass of the target lesion before or on the DUS FU visit. • Lesion patency is defined as freedom from more than 50% stenosis based on DUS PSVR comparing data within the treated segment to the proximal normal arterial segment. • PSVR >2.4 suggests >50% stenosis. | | | | | | PMA P190019: FDA Summary of Safety and Effectiveness Data {35} ![img-4.jpeg](img-4.jpeg) | | Time from Index Procedure (Days) | | | | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | Number of Subjects with Ranger DCB Balloon | 0 | 1-30 | 31-60 | 61-90 | 91-120 | 121-182 | 183-270 | 271-365 | 366-395 | | Entered | 278 | 277 | 276 | 274 | 274 | 271 | 269 | 255 | 195 | | Censored | 1 | 1 | 2 | 0 | 2 | 1 | 11 | 40 | 39 | | Events | 0 | 0 | 0 | 0 | 1 | 1 | 3 | 20 | 15 | | Event Rate | 0% | 0% | 0% | 0% | 0.4% | 0.7% | 1.9% | 10.2% | 17.9% | | Event Free | 100% | 100% | 100% | 100% | 99.6% | 99.3% | 98.1% | 89.8% | 82.1% | | Std Error | 0% | 0% | 0% | 0% | 0.4% | 0.5% | 0.8% | 1.9% | 2.6% | | Number of Subjects with Standard PTA Balloon | 0 | 1-30 | 31-60 | 61-90 | 91-120 | 121-182 | 183-270 | 271-365 | 366-395 | | Entered | 98 | 98 | 98 | 96 | 96 | 94 | 91 | 83 | 59 | | Censored | 0 | 0 | 1 | 0 | 1 | 2 | 2 | 10 | 9 | | Events | 0 | 0 | 1 | 0 | 1 | 1 | 6 | 14 | 6 | | Event Rate | 0% | 0% | 1.0% | 1.0% | 2.1% | 3.1% | 9.6% | 26.0% | 34.1% | | Event Free | 100% | 100% | 99.0% | 99.0% | 97.9% | 96.9% | 90.4% | 74.0% | 65.9% | | Std Error | 0% | 0% | 1.0% | 1.0% | 1.4% | 1.8% | 3.0% | 4.7% | 5.2% | Subjects event-free at 395 days or later are censored at greater than 395 days. Event rate and standard error estimates are for interval end. Standard errors by Greenwood formula. Figure 5: Kaplan-Meier Plot – Primary Patency Through 13 Months, Full Cohort, RCT Intent-to-Treat (N=376 Subjects) PMA P190019: FDA Summary of Safety and Effectiveness Data {36} # 3. Additional Secondary Analyses Secondary endpoints for the full cohort for procedural / technical / clinical success, MAE rate through 60 months, non-serious non-device/procedure- related AE rates, rate of primary and secondary sustained clinical improvemen…
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